CONTRAINDICATIONS
Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin or
other hydantoins.
Additional Information For The Injection: Because of its effect on ventricular
automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second
and third degree A-V block, and patients with Adams-Stokes syndrome.
WARNINGS
Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus.
When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or
substitution of alternative antiepileptic medication arises, this should be done gradually.
However, in the event of an allergic or hypersensitivity reaction, rapid substitution of
alternative therapy may be necessary. In this case, alternative therapy should be an
antiepileptic drug not belonging to the hydantoin chemical class.
There have been a number of reports suggesting a relationship between phenytoin and the
development of lymphadenopathy (local or generalized) including benign lymph node
hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and
effect relationship has not been established, the occurrence of lymphadenopathy indicates
the need to differentiate such a condition from other types of lymph node pathology.
Lymph node involvement may occur with or without symptoms and signs resembling
serum sickness, e.g., fever, rash and liver involvement. In all cases of lymphadenopathy,
follow-up observation for an extended period is indicated and every effort should be
made to achieve seizure control using alternative antiepileptic drugs.
Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use
may decrease serum levels.
In view of isolated reports associating phenytoin with exacerbation of porphyria, caution
should be exercised in using this medication in patients suffering from this disease.
Use in Pregnancy
A number of reports suggest an association between the use of antiepileptic drugs by
women with epilepsy and a higher incidence of birth defects in children born to these
women. Data are more extensive with respect to phenytoin and phenobarbital, but these
are also the most commonly prescribed antiepileptic drugs; less systematic or anecdotal
reports suggest a possible similar association with the use of all known antiepileptic drugs.
The reports suggesting a higher incidence of birth defects in children of drug-treated
epileptic women cannot be regarded as adequate to prove a definite cause and effect
relationship. There are intrinsic methodologic problems in obtaining adequate data on
drug teratogenicity in humans; genetic factors or the epileptic condition itself may be more
important than drug therapy in leading to birth defects. The great majority of mothers on
antiepileptic medication deliver normal infants. It is important to note that antiepileptic
drugs should not be discontinued in patients in whom the drug is administered to prevent
major seizures, because of the strong possibility of precipitating status epilepticus with
attendant hypoxia and threat to life. In individual cases where the severity and frequency
of the seizure disorder are such that the removal of medication does not pose a serious
threat to the patient, discontinuation of the drug may be considered prior to and during
pregnancy, although it cannot be said with any confidence that even minor seizures do not
pose some hazard to the developing embryo or fetus. The prescribing physician will wish
to weigh these considerations in treating or counseling epileptic women of childbearing
potential.
In addition to the reports of increased incidence of congenital malformations, such as cleft
lip/palate and heart malformations, in children of women receiving phenytoin and other
antiepileptic drugs, there have more recently been reports of a fetal hydantoin syndrome.
This consists of prenatal growth deficiency, microcephaly and mental deficiency in
children born to mothers who have received phenytoin, barbiturates, alcohol, or
trimethadione. However, these features are all interrelated and are frequently associated
with intrauterine growth retardation from other causes.
There have been isolated reports of malignancies, including neuroblastoma, in children
whose mothers received phenytoin during pregnancy.
An increase in seizure frequency during pregnancy occurs in a high proportion of patients,
because of altered phenytoin absorption or metabolism. Periodic measurement of serum
phenytoin levels is particularly valuable in the management of a pregnant epileptic patient
as a guide to an appropriate adjustment of dosage. However, postpartum restoration of
the original dosage will probably be indicated.
Neonatal coagulation defects have been reported within the first 24 hours in babies born
to epileptic mothers receiving phenobarbital and/or phenytoin. Vitamin K has been shown
to prevent or correct this defect and has been recommended to be given to the mother
before delivery and to the neonate after birth.
Additional Information for the Injection: IV administration should not exceed 50 mg
per minute. In neonates, the drug should be administered at a rate not exceeding 1-3
mg/kg/min.
Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular
conduction depression and ventricular fibrillation. Severe complications are most
commonly encountered in elderly or gravely ill patients.
Hypotension usually occurs when the drug is administered rapidly by the IV route.
PRECAUTIONS
General
The liver is the chief site of biotransformation of phenytoin; patients with impaired liver
function, elderly patients, or those who are gravely ill may show early signs of toxicity.
A small percentage of individuals who have been treated with phenytoin have been
shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme
availability and lack of induction; it appears to be genetically determined.
Phenytoin should be discontinued if a skin rash appears (see WARNINGS regarding
drug discontinuation). If the rash is exfoliative, purpuric, or bullous or if lupus
erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected,
use of this drug should not be resumed and alternative therapy should be considered.
(See ADVERSE REACTIONS.) If the rash is of a milder type (measles-like or
scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the
rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated.
Phenytoin and other hydantoins are contraindicated in patients who have experienced
phenytoin hypersensitivity. Additionally, caution should be exercised if using structurally
similar (e.g., barbiturates, succinimides, oxazolidinediones and other related compounds)
in these same patients.
Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been
reported. Phenytoin may also raise the serum glucose level in diabetic patients.
Osteomalacia has been associated with phenytoin therapy and is considered to be due to
phenytoin's interference with Vitamin D metabolism.
Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes.
Appropriate diagnostic procedures should be performed as indicated.
Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and
absence (petit mal) seizures are present, combined drug therapy is needed.
Serum levels of phenytoin sustained above the optimal range may produce confusional
states referred to as "delirium," "psychosis," or "encephalopathy," or rarely irreversible
cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are
recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are
excessive; if symptoms persist, termination is recommended. (See WARNINGS.)
Information for the Patient
Patients taking phenytoin should be advised of the importance of adhering strictly to the
prescribed dosage regimen, and of informing the physician of any clinical condition in
which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
Patients should also be cautioned on the use of other drugs or alcoholic beverages
without first seeking the physician's advice.
Patients should be instructed to call their physician if skin rash develops.
The importance of good dental hygiene should be stressed in order to minimize the
development of gingival hyperplasia and its complications.
Laboratory Tests
Phenytoin serum level determinations may be necessary to achieve optimal dosage
adjustments.
Drug/Laboratory Test Interactions
Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may also
produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin
may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl
transpeptidase (GGT).
Carcinogenesis
See WARNINGS section for information on carcinogenesis.
Pregnancy
See WARNINGS section.
Nursing Mothers
Infant breast-feeding is not recommended for women taking this drug because phenytoin
appears to be secreted in low concentrations in human milk.
Additional Information for the Injection: The addition of phenytoin sodium injection,
USP to IV infusion is not recommended due to lack of solubility and resultant
precipitation.
Each injection of phenytoin sodium should be followed by an injection of sterile saline
through the same needle or IV catheter to avoid venous irritation due to the alkalinity of
the solution. Continuous infusion should be avoided. Soft tissue irritation and inflammation
has occurred at the site of injection with and without extravasation of intravenous
phenytoin. Soft tissue irritation varying from slight tenderness to extensive necrosis and
sloughing has been noted. Subcutaneous or perivascular injection should be avoided.